One third of the world's population is infected with Mycobacterium tuberculosis (TB). Annually, more than 9 million become sick, and there are more than 1.5 million TB related deaths. It is one of the leading causes of death in HIV-infected adults. In particular, TB resides and replicates in the lung. Even in BCG vaccinated adults, it normally takes 2 to 3 weeks for T cells, the primary arm of immunity against TB, to respond in the lung. The VRC has developed vaccine strategies to attenuate or possibly prevent pathogenesis following infection with TB by eliciting potent T cell responses at the site of infection, the lung mucosa. Aerosol delivery of antigens has proven to be a potent immunization scheme in the lung; the VRC has extensive experience with such delivery in the nonhuman primate model and has shown strong immune responses protective against influenza and SIV pathogenesis by such a modality. In addition, VRC data show that very strong T cell responses are elicited that remain relatively stable in the lung for a year or more in nonhuman primates. Based on these data, the VRC will evaluate the hypothesis that aerosol delivery of TB antigens to the lung will provide more rapid and potent T-cell responses compared to standard BCG vaccination, resulting in decreased pathogenesis and/or attenuated infection by TB. To test this hypothesis, detailed research studies in a suitable animal model will be performed. The choice of species, TB challenge strain, challenge delivery route, and other variables will be studied.